Obstructive sleep apnea (OSA) is a clinical syndrome characterized by repeated episodes of severe hypoxemia caused by intermittent closure of the upper airway during sleep. Complications of OSA include pulmonary hypertension caused by vascular remodeling in the lung. Repeated intermittent hypoxia is the most likely cause of this remodeling. The remodeling responses to hypoxia imply that a cellular O2 sensor exists that is capable of responding to rapid changes in [O2]. Studies from this laboratory indicate that mitochondria function as O2 sensors during hypoxia in diverse cells, releasing reactive oxygen species (ROS) to the cytoplasm that trigger intracellular signaling pathways leading to the activation of the transcription factors Nuclear Factor kappa B (NFkB) and Hypoxia-Inducible Factor (HIF- 1) in some cells, and that mediate adaptive metabolic responses in others. This application proposes that mitochondria also function as O2 sensors during intermittent hypoxia, by releasing ROS that lead to the activation of the transcription factors NFkB, HIF- I and AP- I that regulate genes involved in long-term vascular remodeling. Growth factors contribute to proliferation of cells in the vascular wall, and hypoxia amplifies their mitogenic response via an unknown mechanism. Mitochondrial ROS released during hypoxia could amplify the mitogenic response to growth factors by augmenting the oxidant signaling required for their proliferative response.
Aim I will determine whether mitochondria function as O2 sensors by releasing ROS during intermittent hypoxia.
Aim 2 will determine whether these ROS are necessary and sufficient for the activation of the transcription factors NFkB, HIF- I and AP- 1, and whether these factors mediate the subsequent transcriptional activation of target genes involved in vascular remodeling.
Aim 3 will determine whether intermittent hypoxia amplifies the proliferative response to mitogens by stimulating mitochondrial ROS generation that augments growth factor-induced non-mitochondrial oxidant signaling. Collectively, these studies could identify a novel mechanism of O2 sensing in the lung, and provide a mechanistic explanation for the activation of gene transcritpion and cellular proliferation during intermittent hypoxia.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL066315-02
Application #
6391208
Study Section
Special Emphasis Panel (ZHL1-CSR-H (S1))
Program Officer
Garfinkel, Susan J
Project Start
2000-09-30
Project End
2004-08-31
Budget Start
2001-09-01
Budget End
2002-08-31
Support Year
2
Fiscal Year
2001
Total Cost
$263,328
Indirect Cost
Name
University of Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
225410919
City
Chicago
State
IL
Country
United States
Zip Code
60637
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Waypa, Gregory B; Osborne, Scott W; Marks, Jeremy D et al. (2013) Sirtuin 3 deficiency does not augment hypoxia-induced pulmonary hypertension. Am J Respir Cell Mol Biol 49:885-91
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Loor, Gabriel; Kondapalli, Jyothisri; Schriewer, Jacqueline M et al. (2010) Menadione triggers cell death through ROS-dependent mechanisms involving PARP activation without requiring apoptosis. Free Radic Biol Med 49:1925-36
Waypa, Gregory B; Schumacker, Paul T (2010) Hypoxia-induced changes in pulmonary and systemic vascular resistance: where is the O2 sensor? Respir Physiol Neurobiol 174:201-11
Guzy, Robert D; Mack, Matthew M; Schumacker, Paul T (2007) Mitochondrial complex III is required for hypoxia-induced ROS production and gene transcription in yeast. Antioxid Redox Signal 9:1317-28
Iwase, Hirotaro; Robin, Emmanuel; Guzy, Robert D et al. (2007) Nitric oxide during ischemia attenuates oxidant stress and cell death during ischemia and reperfusion in cardiomyocytes. Free Radic Biol Med 43:590-9
Robin, Emmanuel; Guzy, Robert D; Loor, Gabriel et al. (2007) Oxidant stress during simulated ischemia primes cardiomyocytes for cell death during reperfusion. J Biol Chem 282:19133-43

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